EP0910360, U.S. Pat. No. 6,147,094, EP0936915, U.S. Pat. No. 6,258,828, EP1054670, U.S. Pat. No. 6,310,051, EP1060174, U.S. Pat. No. 6,391,895 disclose the use of dipyridoxyl based chelating agents and their metal chelates and the use of certain manganese containing compounds, in particular manganese chelates, in medicine. The use of such compounds as cell protective agents in cancer therapy is also disclosed. The above cited documents disclose that certain chelating agents, in particular dipyridoxyl and aminopolycarboxylic acid based chelating agents, and their metal chelates are effective in treating or preventing anthracycline-induced cardiotoxicity, ischaemia-reperfusion-induced injuries and atherosclerosis. Dipyridoxyl based chelating agents and their chelates with trivalent metals have previously been described by Taiferro (Inorg. Chem. 1984; 23:1183-1192).
DPDP (N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid), and the dephosphorylated counterpart PLED (N,N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid) are dipyridoxyl compounds able to chelate metals. It has previously been described that the manganese chelates of these compounds, MnDPDP and its dephosphorylated counterpart MnPLED, possess catalytic antioxidant activity, i.e., a superoxide dismutase (SOD) mimetic activity. These compounds have been shown to have a protective effect in normal cells e.g., against the cytostatic drug doxorubicin and ischemia-reperfusion. It is the SOD mimetic activity, which is an inherent property of redox-active manganese (Mn2+/Mn3+) bound to DPDP/PLED (Brurok et al., Biochem Biophys Res Commun. 1999; 254:768-721), that explains the protective effects. Consequently, Brurok and co-workers (1999) have shown that the PLED metal complex loses its catalytic activity after replacing redox-active manganese with redox-inactive zinc (Zn2+).
Laurent et al. (Cancer Res. 2005; 6:948-56) and Alexandre et al., (J Natl Cancer Inst. 2006; 98:236-44) have recently described that MnDPDP (equivalent to the ready-to-use MRI contrast agent Teslascan) not only increased survival of normal cells but also increased cancer cell death during cytostatic treatment, e.g., with oxaliplatin. Cytostatic drugs may cause cancer cell death by elevating intracellular H2O2 and inducing apoptosis. The Laurent et al., hypothesis was that MnDPDP due to its SOD mimetic activity elevated intracellular H2O2 and hence acted in synergy with cytostatic drugs. Since the basal level of H2O2 is much lower in normal cells compared to cancer cells, the authors suggested that elevation from a low H2O2 level induced cell survival in normal cells. They furthermore suggested that elevation from a much higher basal level of H2O2 in cancer cells at the same time resulted in apoptotic signalling and hence cell death. Consequently, these authors suggested that both these effects, i.e., the increase in cancer cell death and survival of normal cells, were caused by the SOD mimetic activity of MnDPDP, an activity which is absolutely dependent on redox-active manganese. It has also been shown that intravenous injection of both the mother compound MnDPDP and its metabolite MnPLED into mice gave rise to protection against certain cytostatic drugs (EP0910360 and U.S. Pat. No. 6,147,094).
When MnDPDP is intravenously injected into humans about 70% of the administered manganese is released. For diagnostic imaging use and for occasional therapeutic use, dissociation of manganese from MnDPDP represents no major problem. However, for more frequent use accumulated manganese toxicity may represent a serious toxicological problem, particularly when it comes to neurotoxicity (Crossgrove & Zheng; NMR Biomed. 2004; 17:544-53). Thus, for frequent therapeutic use, as in cancer treatment, compounds that dissociate manganese should be avoided.
A number of anti-tumour agents are associated with adverse side effects. Paclitaxel, for example, is one such cytostatic drug which has shown anti-neoplastic activity against a variety of malignant tissues, including those of the breast. However, at the dosages required to have an anti-neoplastic effect, paclitaxel has a number of adverse side-effects which include cardiovascular irregularities as well as haematological and gastrointestinal toxicity. Oxaliplatin, in particular in combination with 5-fluorouracil (5-FU), is another example of a cytostatic drug that is effective in the treatment of colorectal cancer but its use is restricted by severe adverse side-effects, in particular haematological toxicity and neurotoxicitiy. Severe side-effects also restrict the use of radiation therapy in cancer.
There is hence an unmet medical need to find new chemotherapeutic drugs with fewer side-effects, in addition to find methods to protect normal cells against injuries caused by cancer treatment.